P1263: SINGLE NUCLEOTIDE POLYMORPHISMS IN PATIENTS WITH ENDOTHELIAL DAMAGE AFTER PEDIATRIC ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION
Authors: Lilli Leimi, Jessica Koski, Kim Vettenranta, Inkeri Lokki, Seppo Meri
Journal: HemaSphere (2023)

Topic: 22. Stem cell transplantation - Clinical Background: In a retrospective, single-center study, we analyzed endothelial damage as a potential, common mechanism for the adverse effects in pediatric HSCT. We evaluated the prevalence of key vascular complications and graft-versus-host disease among 122 patients with an allogeneic HSCT (2001-2013) at the Helsinki University Children´s Hospital, Finland. We identified a total of 19/122 (15.6%) patients with vascular complications, fulfilling the criteria of capillary leak syndrome (CLS), veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) or thrombotic microangiopathy (TMA). These patients had a poorer overall survival (77% versus 26%, p<0.001). These endotheliopathy-related adverse events appeared early on post-HSCT, varied in their clinical phenotype and predicted a poor outcome. Aims: Our aim was to describe potential mechanisms behind the acute complications seen post-HSCT. Methods: We executed whole exome sequencing (WES) using next generation sequencing (NGS) on 118 patients having an adequate pretransplantation DNA for analysis to define possible variations and mutations potentially exposing to the activation of the complement system. In data analysis, we focused on 57 genes coding for components of the complement system. Results: 58 out of 118 patients (49.1%) had one or several, nonsynonymous single nucleotide polymorphisms (SNP) and altogether 63 coding variants in complement genes. 21/78 (26.9%) of the SNPs was in the terminal pathway. Patients with endotheliopathy had variants in four different complement genes: in the terminal pathway (C9 and C6), lectin pathway (MASP1) and regulator ITGAM. Four patients had the same rare (ExAC EUROPE MAF=0.00164) missense SNP (rs183125896; Thr279Ala) in C9 gene. Three of these patients were diagnosed with endotheliopathy, one with capillary leak syndrome (CLS) and two with CLS followed by thrombotic microangiopathy (TMA). Two of these patients had only this C9 variant, one also a variant in C1s (rs149869489). This C9 variant has no previously known disease associations and is classified by the ACMG guidelines as a variant of uncertain significance (VUS). We conducted a gene burden test with gnomAD Finnish (fin) as the reference population. We investigated complement gene variants seen in our patient population and Total Frequency Testing (TFT) was used for execution of burden tests. Gene variants seen in our patients with endotheliopathy were all significantly (FDR < 0.05) enriched compared to gnomAD. Overall, 18/31 genes coding for components of the complement system had an increased burden of missense variants among patients in comparison to the gnomAD fin population controls (N=10 816) Summary/Conclusion: Injury to the vascular endothelium is relatively common after HSCT with varying phenotypic appearances suggesting hitherto unidentified underlying mechanisms. These nonsynonymous SNPs in complement genes may be related to endotheliopathy and poor prognosis seen in these patients. Keywords: Thrombotic microangiopathy, Genetic polymorphism, Endothelial dysfunction, Allogeneic hematopoietic stem cell transplant